Loss of estrogen receptor alpha promotes distant metastasis through epithelial-mesenchymal transition in luminal-type breast cancer

Breast cancer (BC) is a global health challenge, with approximately 75 % of cases classified as estrogen receptor alpha (ER-α)-positive luminal subtype. Although hormone therapies such as tamoxifen have improved outcomes, a subset of ER-α-positive BC patients develop resistance, resulting in early metastasis. Our research shows that ER-α loss is more frequent in distant metastases and is associated with poorer survival. We investigated the role of ER-α expression in BC progression, metastasis, and recurrence using comprehensive in vitro and in vivo models. Low ER-α expression in primary tumors was associated with increased metastasis and recurrence in ER-α-positive BC. Luminal BC cells with low ER-α expression exhibited increased invasiveness, whereas ER-α overexpression in triple-negative BC cells suppressed metastatic behavior. Mechanistically, ER-α downregulation promoted epithelial-mesenchymal transition (EMT) and upregulated MMP9 expression in BC cells. These findings suggest that ER-α loss facilitates BC metastasis through the EMT process. Relatively low ER-α expression may serve as a potential prognostic indicator in ER-positive luminal BC. These results have potential implications for predicting outcomes in ER-positive BC and highlight the importance of personalized treatment strategies. • Novel scoring system links ER-low tumors to distant metastasis risk. • Low ER-α expression enhances EMT and MMP9, promoting tumor invasiveness. • ER-α overexpression in TNBC inhibits metastasis, revealing therapeutic potential. • Low ER expression may be a prognostic marker for “ER-low-positive” BC patients.